This Program Project has supported a multidisciplinary program of research since 1987, focused on various aspects of aging and dementia in the adult population with mental retardation. The aging of adults with Down syndrome (DS) has received special attention due to their reduced life expectancy and dramatically increased risk of Alzheimer' disease (AD). Based upon the foundation provided by our previous work, we now seek to extend our program of research to address several issues of major significance by focusing on individuals with DS. Our Program Project will include five Subprojects supported by two Cores, and major areas of investigation will focus on: (a) factors that influence individual risk for AD within the DS population, (b) the emergence of maladaptive behaviors as dementia develops and as declines in cognition and function progress, (c) development of objective measures of functional and cognitive abilities that can be used for valid classification/diagnosis of dementia in the population with DS, (d) morphometric studies of motor system pathology throughout the lifespan of individuals with DS, and (e) the influence of lifespan development and AD associated pathology on gene expression within specific brain structures of individuals with DS. Our overall program has always included a balanced mixture of work. Some of our studies were designed to describe aging and dementia within our target population, while other studies focused on basic biological processes playing key roles in risk for and progression of AD. Over the next five years, we plan to shift this balance toward issues that have more direct implications for diagnosis, treatment and prevention of AD, both for adults with DS and more broadly. As in the past, our activities will be enhanced by the interactions among a large team of investigators representing diverse disciplines, including epidemiology, genetics, immunology, molecular biology, neurology, neuropathology, psychiatry, psychology and statistics. It is this multidisciplinary environment that has enabled us to conduct the research we have generated in the past, and the work we are now proposing would be exceedingly difficult, perhaps impossible to do in any other context.